Method for attenuating free radical formation resulting from a bodily insult

ABSTRACT

A method is provided for attenuating free radical formation resulting from a bodily insult. The method includes administering bicarbonate to the body of a subject at a dosage ranging from 1.5 mEq/kg of body weight to 5.0 mEq/kg of body weight within a 24-hour period.

TECHNICAL FIELD AND BACKGROUND OF THE INVENTION

This invention relates generally to a method for attenuating freeradical formation resulting from a bodily insult, and more specifically,to a method for protecting nephrons against injury caused by disruptionof a chemical environment in the kidneys. The method protects thenephrons by administering a prophylactic solution into the body tocounter an effect of the kidneys' acid-base balance on an anticipateddisruption of the kidney function. In one particular application, theinvention is a method of administering a radiographic contrast medium ina manner which reduces the incidence of contrast-induced nephropathy(CIN).

The kidneys' main function is to eliminate excess fluid and wastematerial from the blood. When the kidneys lose this filtering ability,dangerous levels of fluid and waste accumulate in the body causingkidney (renal) failure. Acute kidney failure is most likely to happenafter complicated surgery or severe injuries, or when blood vesselsleading to the kidneys become blocked or experience low blood pressure,or when the kidneys are exposed to chemical compounds that arepotentially toxic. Conversely, chronic kidney failure usually developsslowly with few symptoms in the early stages. Many people with chronickidney failure have no symptoms until their kidney function hasdecreased to less than 25 percent of normal. High blood pressure anddiabetes are the most common causes of chronic kidney failure.

A single adult kidney contains roughly a million nephrons, eachconsisting of a tuft of capillary blood vessels (glomerulus) and tubulesthat lead to the collecting system and, eventually, to the bladder. Eachtuft of capillaries filters fluid from the bloodstream, and passes thefiltrate to a tubule. The filtrate contains both waste products andsubstances vital for health. From the tubules, waste byproducts such asurea, uric acid and creatinine are excreted in urine while substancesthe body needs such as glucose, proteins, amino acids, calcium and saltsare absorbed by the tubules back into the bloodstream. While this uniquefiltration system is generally able to clear all the waste productsproduced by the body, problems can occur if the fragile tubules orglomeruli are damaged or diseased.

Many conditions and circumstances can damage kidneys, includingintrinsic kidney disease or injury, high blood pressure, diabetesmellitus, exposure to toxins and certain medications, kidney stones,tumors and even infections in other parts of your body. Many of thesemay show no signs or symptoms until irreparable damage has occurred.

The mechanism of the vast majority of acute kidney damage and injury isoften modulated by the intra-kidney formation of free radicals known tobe increased in an acid environmental (pH that is low), as compared tonormal body pH. One of the functions of the kidney is to regulateacid-base metabolism by actively absorbing the filtered bicarbonate andgenerating bicarbonate, while excreting the typical acid load ofsubjects. This process of eliminating the “acid load” causes thegeneration of renal tubular fluid which is relatively acidic compared tonormal tissue. This acid environment could accelerate the formation offree radicals under certain conditions. Existing medical referencessupport the attenuation of free radical formation by inducing a morenormal pH environment in the kidney.

The use of iodinated, radiographic contrast (RC) media has long beenrecognized as a contributing factor in acute kidney dysfunction.Examples of imaging and medical procedures requiring the use of RCinclude Computerized Tomographic (“CT”) scan enhancement, arteriograms,cardiac catherization, vascular studies, stents, lumbar myelography,thoraco-cervical myelography, cerebral angiography, peripheralarteriography, venography, angiocardiography, left ventriculography,selective visceral arteriography, digital subtraction abgiography,urography, arthrography, and computer tomography angiography (“CTA”).The degree of acute kidney dysfunction—labeled “contrast inducednephropathy” (CIN)—ranges from a short-term slight increase in serumcreatinine levels to overt kidney failure requiring temporary orpermanent dialysis, and in some cases resulting in death. CIN is broadlydefined as a rise in serum creatinine levels in relation to theadministration of contrast media. CIN has been reported to be the thirdmost common cause of kidney insufficiency occurring in hospitalizedpatients, and it might be a factor in up to 10 percent of all cases ofacute kidney failure.

Prior art efforts to treat kidney dysfunction recognize the use of asodium bicarbonate infusion. These existing methods, however, arefraught with complications, drawbacks, and inconclusive test results.

Complications of Bicarbonate Infusions

Hypertonic solutions of sodium bicarbonate (8.4% or 1 Molar) aresupplied in most hospitals in 50 ml ampules to be administered slowly,or added to other intravenous solutions. Rapid infusions or excessivevolumes of this hypertonic solution are known to cause serious injury.This injury can occur in the form of a rapid depression of serumpotassium and subsequent cardiac rhythm disturbances (even fataldisturbances), depression of serum ionized calcium with an associateddrop in blood pressure, hemolysis or breakdown of red cells as a resultof the high osmolar solution, and severe pain and tissue necrosis at thesite of an intravenous extravagation.

If sodium bicarbonate is prepared in a solution with a concentration of25 to 50 mEq/L, as directed in prior U.S. Pat. No. 5,112,622, then thevolume required to reach a target level of 2 mEq/kg (of subject weight)in a 70 kg subject would be 5.6 to 2.8 L. This volume is large and achallenge for normal subjects to handle in an eight hour period, butentirely unacceptable and dangerous as an administered dose of fluids to“sick” or elderly subjects undergoing a substantial medical procedure,such as cardiac catheterization or cardiac surgery. The critical careliterature is full of references to the danger of sodium bicarbonateinfusions in critically ill subjects.

The bicarbonate pretreatment of the present invention has been shown tonearly eliminate acute kidney failure associated with contrast exposure.Similar evidence shows that similar doses can reduce the acute kidneyfailure associated with cardiovascular surgery. The choice ofbicarbonate concentration in the 100 to 300 mEq/L range allows aneffective dose of solution to be administered in a volume of fluid thatis well tolerated by “sick” subjects undergoing the diagnostic ortherapeutic procedure.

Since many other causes of kidney dysfunction (other than CIN andischemia from low blood pressure) are induced by the free radicalformation process, the present method can also be expected to respondfavorably against these disruptions by similar administration ofbicarbonate, provided excessive volume and excessive concentration canbe avoided. Suggested prior art treatments using sodium bicarbonate,such as described in the '622 patent, would require a volume of fluid inexcess of what even a normal subject could be expected to toleratewithout death or serious complications. The present invention hasidentified an effective and tolerable dose of the bicarbonate anion,concentration of the anion, and timely administration necessary for asuccessful prophylaxis.

SUMMARY OF INVENTION

Therefore, it is an object of the invention to provide a method forprotecting nephrons against injury caused by disruption of the chemicalenvironment in the kidneys.

It is another object of the invention to provide a method for protectingnephrons against injury caused by administration of iodinated,radiographic contrast (RC) media.

It is another object of the invention to alter the kidney tubularacid-base balance in favor of a more normal pH prior to a bodily insultor chemicals in order to attenuate kidney damage.

It is another object of the invention to provide a method foradministering a contrast medium which substantially eliminates theincidence of contrast-induced nephropathy (CIN).

It is another object of the invention to provide a method foradministering a contrast medium which reduces the subject's time in thehospital by 12 hours or more, as compared to other treatments whichinfuse saline solution for 12 hours before and 12 hours after thecontrast exposure.

It is another object of the invention to provide a method foradministering a contrast medium which utilizes a renoprotectivebicarbonate received intravenously or orally.

It is another object of the invention to provide a method foradministering a contrast medium which is especially applicable tochronically ill subjects who currently may not receive a contrast mediumfor fear of inducing CIN.

It is another object of the invention to provide a method foradministering a contrast medium in a manner which will improve ahealthcare institution's rating for insurance and referral purposes.

It is another object of the invention to provide a method foradministering a contrast medium in a manner which reduces thephysician's exposure to legal liability.

It is another object of the invention to provide a method foradministering a contrast medium in a manner which will reduce overallhealthcare costs.

It is another object of the invention to provide a method foradministering a contrast medium in a manner which will not damage orimpair healthy kidneys.

It is another object of the invention to provide a method foradministering a contrast medium in a manner which is easily administeredby the hospital staff.

It is another object of the invention to provide a method foradministering a contrast medium which is applicable to both ionic andnon-ionic contrast media.

It is another object of the invention to provide a method forattenuating free radical formation in the body of a subject.

It is another object of the invention to provide a method which reducesthe anion gap in the arterial blood.

These and other objects of the present invention are achieved in thepreferred embodiments disclosed below by providing a method forprotecting nephrons against injury caused by disruption of a chemicalenvironment in the kidney. The method includes the step of administeringa prophylactic alkaline solution into the body of a subject. Thesolution has a concentration of bicarbonate greater than 70 mEq/L.

Preferably, the prophylactic solution has a bicarbonate concentrationwithin a range of 100 mEq/L and 300 mEq/L. The bicarbonate isadministered into the body at a dose of between 0.8 and 5 mEq ofbicarbonate per kg of subject weight, and more preferably, between 1.5and 3 mEq of bicarbonate per kg of subject weight.

According to another preferred embodiment of the invention, theprophylactic solution contains sodium.

According to another preferred embodiment of the invention, theprophylactic solution contains potassium.

Preferably, the prophylactic solution contains between 75%-100% sodiumand between 25%-0% potassium.

According to another preferred embodiment of the invention, the totalvolume of prophylactic solution administered into the body ranges from 4to 30 ml/kg (of subject weight).

According to another preferred embodiment of the invention, theprophylactic solution is administered into the body at a rate of between0.5 and 2.5 ml/kg (of subject weight)/hr.

In another embodiment, the invention is a method for reducingcontrast-induced nephropathy resulting from administration of a contrastmedium into the body of a subject. The method includes the steps of,prior to receiving the contrast medium, administering an initial dose ofprophylactic alkaline solution into the body. The solution has aconcentration of bicarbonate greater than 70 mEq/L. After receiving thecontrast medium, a maintenance dose of the prophylactic solution isadministered into the body.

According to another preferred embodiment of the invention, themaintenance dose is administered into the body at a rate lower than thatof the initial dose.

According to another preferred embodiment of the invention, the initialdose of prophylactic solution is administered into the body at a timebeginning no later than 3 hours and no less than 15 minutes prior toreceiving the potential bodily insult.

According to another preferred embodiment of the invention, themaintenance dose is administered into the body for a period of between 5and 12 hours after receiving the potential bodily insult.

In yet another embodiment, the invention is a method for administering acontrast medium into the body of a subject. The method includes thesteps of, prior to receiving the contrast medium, administering aninitial dose of prophylactic alkaline solution into the body. Thesolution has a concentration of bicarbonate greater than 70 mEq/L. Thecontrast medium is then administered into the body. After receiving thecontrast medium, a maintenance dose of the prophylactic solution isadministered into the body.

In yet another embodiment, the invention is a method for attenuatingfree radical formation resulting from a bodily insult. The methodincludes the step of administering an alkaline solution into the body ofa subject. The solution has a concentration of bicarbonate greater than70 mEq (milliequivalents)/L.

According to one embodiment, the bodily insult comprises sepsis orseptic shock syndrome.

According to another embodiment, the bodily insult is ischemia—usuallythis is a state of low blood pressure as a result of one or more of manydifferent medical conditions.

According to another embodiment, the bodily insult is a conditionselected from the group consisting of immunosuppression, rhabdomyolysis,heat stroke, acidosis, heart failure, blood clot, pulmonary embolism,pneumonia, shock, trauma, and low blood pressure.

According to another embodiment, the bodily insult is a reaction causedby a drug selected from the group consisting of antibiotics andnonsteroidal anti-inflammatory drugs (NSAIDs).

According to another embodiment, the bodily insult is a reactionresulting from treatment of cancer using chemical agents.

According to another embodiment, the bodily insult is cell lysis.

According to another embodiment, the bodily insult is any surgery.

According to another embodiment, the bodily insult is an organtransplant, or results from reperfusion insult associated with kidneytransplantation.

According to another embodiment, the bodily insult is cardiovascular orvascular surgery.

According to another embodiment, the solution is administered into thebody during trauma care. The term “trauma care” is broadly defined tomean an initial medical response to an injury, such at that performed atthe scene of the accident, in an ambulance, or at the emergency room.

According to another embodiment, the bodily insult is a drug overdose.

According to another embodiment, the bodily insult is radiation exposureresulting from radiation therapy, whether the exposure was the result ofmedical therapy or exposure at the work place.

In yet another embodiment, the invention is a method for manipulating anacid-base balance in the body. The method includes the step ofadministering an alkaline solution into the body of a subject. Thesolution has a concentration of bicarbonate greater than 70 mEq/L.

In yet another preferred embodiment, the invention includes the step ofadministering bicarbonate to the body of a subject at a dosage of atleast 1.5 mEq/kg of body weight within a 24-hour period.

According to another preferred embodiment of the invention, between 75%to 100% of the bicarbonate dosage is administered within a 12-hourperiod.

According to another preferred embodiment of the invention, between 75%to 100% of the bicarbonate dosage is administered within a 6-hourperiod.

According to another preferred embodiment of the invention, between 25%to 40% of the bicarbonate dosage is administered prior to the bodilyinsult. A remaining 60% to 75% of the bicarbonate dosage is administeredat hourly intervals after the bodily insult.

According to another preferred embodiment of the invention, the dosageof bicarbonate is at least 3 mEq/kg of body weight.

According to another preferred embodiment of the invention, thebicarbonate is administered in a form selected from a group consistingof tablet, powder, capsule, and solution.

DESCRIPTION OF THE PREFERRED EMBODIMENT AND BEST MODE

The invention is a method for protecting nephrons against injury causedby a disruption of a chemical environment in the kidney. Suchdisruptions commonly result from exposure to iodinated radiographiccontrast media (administered prior to CT scans); emergency exploratorysurgeries; shock; trauma; certain transplant immunosuppression regimens(e.g., cyclosporine and Prograf®); organ transplant; cardiovascularsurgery; certain antibiotic therapy (gentamicin, tobramicin, amikacin,vancomycin); and NSAID's (Motrin®, Indocin®, tordol, Advil®, naprasyn).In its broadest application, the concept of the present method isapplicable for protecting any organ by manipulating the body's acid-basebalance through infusion of a prophylactic alkaline solution in aprescribed concentration and dosage.

The alkaline solution is contained inside a sterile container and isadministered into the body either intravenously or orally. In theexample described below, the method is a prophylactic treatment forpreventing kidney damage resulting from exposure to contrast media.Examples of such iodinated radiographic contrast media include iopamidol(a tri-iodinated, non-ionic, water-soluble, contrast medium), iomeprol,iohexol, iobitridol, iodixanol, ioversol, ioxaglate, iotrolan,iopromide, iobitridol, and diatrizoate. The treatment conditions thenephrons in the kidney to become more alkaline in order to bettertolerate stress caused by the iodinated contrast media. By this method,the goal is to provide between 25% and 40% of the total dose of theprophylactic solution over a time period beginning at least 15 minutesprior to receiving the contrast medium. The remainder of the total doseof the solution is administered during IV infusion of the contrastmedium and over a subsequent 5 to 12 hour period. The total dose ispreferably between 0.8 and 5 mEq of bicarbonate per kilogram of subjectweight, and more preferably, between 1.5 and 3 mEq of bicarbonate perkilogram of subject weight.

According to one embodiment, the solution comprises a bicarbonate anioncombined with a sodium and/or potassium cation. The cation is preferablya mixture of sodium (75% to 100%, typically 235 mEq/L) and potassium(25% to 0%, typically 15 mEq/L). The preferred concentration of thebicarbonate anion is greater than 70 mEq/L, and more preferably, between100 mEq/L and 300 mEq/L. Contrary to the teachings of the prior art, ahigher bicarbonate concentration is desirable in order to infuse thenecessary chemicals without flooding the body with an excessive volumeof fluid. Ideally, the concentration should be around 100 to 300 mEq/L,so that the total volume infused is from 4 to 30 ml/kg (of subjectweight). For a goal infusion of 1.8 mEq/kg (of subject weight) using 250mEq/L solution, the volume infused over a 7 to 8 hour period is 7.2ml/kg (of subject weight)—or an average of 1 ml/kg (of subjectweight)/hour.

Example

A prophylactic solution consisting of 5.41 grams of sodium, 0.59 gramsof potassium, 15.25 grams of bicarbonate, and approximately 979 grams ofwater per liter is prepared and administered into the body via an IVinfusion. The treatment is provided as follows:

(a) at least one hour prior to (but not more than three hours before)intravenous infusion of the iodinated contrast medium, infuse an initialbolus dose of prophylactic solution at a rate of 2.5 mL per kilogram ofsubject weight over 30 to 60 minutes;

(b) after the initial bolus infusion, reduce the infusion rate to 0.62mL per kilogram of subject weight per hour, and continue infusionthroughout administration of the contrast medium and for six (6) hoursafter the contrast administration is completed;

(c) monitor subject during the infusion period for occurrence of adversesymptoms or signs including severe hypertension, pulmonary edema,decompensated heart failure, shortness of breath and wheezing; and

(d) upon occurrence of adverse symptoms or signs, reduce the infusionrate to 10 mL per hour and seek medical evaluation for the subject.

The following Table indicates the prescribed subject dosage rate for theinitial bolus and maintenance infusion:

Initial Bolus, Maintenance Subject Weight mL Infusion Rate, kilograms,kg pounds, lbs over 1 hour mL per hour <32.8 kg <72.2 lbs 2.5 X wt(kg)0.62 X wt(kg) 32.8 to 40.8 kg 72.2 to 89.8 lbs 100 mL 25 mL/hr 40.8 to48.8 kg 89.8 to 107.5 lbs 122 mL 30 mL/hr 48.9 to 56.9 kg 107.6 to 125.2lbs 142 mL 35 mL/hr 57.0 to 64.9 kg 125.3 to 142.9 lbs 162 mL 40 mL/hr65.0 to 73.0 kg 143.0 to 160.7 lbs 182 mL 45 mL/hr 73.1 to 81.0 kg 160.8to 178.4 lbs 202 mL 50 mL/hr 81.1 to 89.1 kg 178.5 to 196.2 lbs 223 mL55 mL/hr 89.2 to 97.2 kg 196.3 to 213.9 lbs 243 mL 60 mL/hr 97.3 to105.2 kg 214.0 to 231.6 lbs 263 mL 65 mL/hr 105.3 to 113.3 kg 231.7 to249.4 lbs 283 mL 70 mL/hr 113.4 to 121.4 kg 249.5 to 267.1 lbs 303 mL 75mL/hr 121.5 to 129.4 kg 267.2 to 284.9 lbs 323 mL 80 mL/hr 129.5 to137.5 kg 285.0 to 302.6 lbs 343 mL 85 mL/hr 137.6 to 145.6 kg 302.7 to320.4 lbs 363 mL 90 mL/hr 145.7 to 153.6 kg 320.5 to 338.1 lbs 383 mL 95mL/hr 153.7 to 161.7 kg 338.2 to 355.8 lbs 403 mL 100 mL/hr >161.7kg >355.8 lbs 2.5 X wt(kg) 0.62 X wt(kg)

In addition to the above, the prophylactic solution may include one or acombination of the following additives: calcium-HCO3, magnesium,dextrose (1%-7%), Na or K lactate (1-60 mEq/L), Na or K citrate oracetate (1-60 mEq/L), acetazolamide, and/or other anionic componentssuch as chloride, phosphate, pyruvate, and/or other unnamed organicanions.

In other applications, the present method may be used to attenuate freeradical formation in the body resulting from a variety of insults. Asindicated above, free radical formation can lead to serious medicaldisorders and conditions including (but not limited to) acute kidneyfailure.

In one example, the present bicarbonate solution is administered tocertain at-risk hospital patients for sepsis—a severe illness caused byoverwhelming infection of the bloodstream by toxin-producing bacteria.Sepsis occurs in 2 of every 100 hospital admissions, and can originateanywhere in the body including the kidneys, liver, gall bladder, bowel,skin, and lungs. The death rate can be as high as 60% for people withunderlying medical problems. Preferably, the initial bolus (as indicatedin the Table above) is administered prior to the bodily insult (sepsis),or immediately after diagnosis, and followed by the prescribedmaintenance infusion for the particular subject until the critical phaseof the infection has resolved (this is usually 2 to 4 days but could beshorter or longer).

In another example, the bodily insult may comprise any ischemiccondition, such as ischemic cardiomyopathy (heart failure). Otherconditions known to cause ischemia include pluggage in the blood system,blood clot, pulmonary embolism, and pneumonia. Again, the initial bolusis preferably administered prior to the bodily insult, or immediatelythereafter, followed by the prescribed maintenance infusion for theparticular subject until the critical phase of the bodily insult hasresolved (this is usually 2 to 4 days but could be shorter or longer).

In yet another example, the bodily insult is an induction ofimmuno-suppression. Subjects with this disorder have a reduced or absentimmune response. Drugs linked to this disorder include cyclosporine-Aand tacrolimus, both known to cause free-radical mediated renal failure.To attenuate free radical formation, an initial bolus of theprophylactic bicarbonate solution is administered to the subject priorto receiving the drug, followed by the prescribed maintenance infusionuntil the critical phase of the induction of immuno-suppression iscompleted (this is usually 2 to 7 days but could be shorter or longer).

Other disorders and conditions, including rhabdomyolysis, acidosis, heatstroke, low blood pressure, heart attack, shock, and trauma promoteincreased free radical formation in the body. In these cases, freeradical formation may be attenuated by administration of an initialbolus of the prophylactic solution prior to the bodily insult followedby the prescribed maintenance infusion. Given the relative difficulty(and in some cases, impossibility) of predicting when such disorders orconditions might occur, the prophylactic solution may be administeredshortly after diagnosis with considerable but perhaps lessereffectiveness, and continued until the critical phase of the bodilyinsult has resolved (this is usually 2 to 4 days but could be shorter orlonger).

All surgeries, especially organ transplants, cardiovascular surgery, andtrauma surgery, promote free radical formation in the body. In thesecases, free radical formation may be attenuated by administration of aninitial bolus of the prophylactic bicarbonate solution prior to surgeryfollowed by the prescribed maintenance infusion and continued until thecritical phase of the bodily insult has resolved (this is usually 1 to 3days but could be shorter or longer).

The present method is further applicable as a prophylactic treatmentwith certain drug therapies including antibiotics and chemotherapy. Forexample, prior to the anticipated cell lysis from chemotherapy, aninitial bolus of bicarbonate solution is administered to the subjectfollowed by the prescribed maintenance infusion. In the case of a drugoverdose, early infusion of the bicarbonate solution in the ambulance oremergency room will protect against acute kidney failure, and may savelives.

Oral Administration of Bicarbonate

Effective attenuation of free radical formation resulting from bodilyinsult may also be achieved through oral administration of a bicarbonatecompound in a manner consistent with the present method. Oraladministration is especially appropriate for healthier subjects with thecapacity to resume normal activity shortly after the insult, whiletaking the prescribed bicarbonate treatment. For these subjects,treatment can be self-administered outside of the hospital orphysician's office, and at a considerably lower cost.

As previously indicated, the total bicarbonate dosage administered tothe body is between 0.8 to 5 mEq per kg of subject weight, and morepreferably, between 1.5 and 3 mEq per kg of subject weight. The examplesbelow use a dosage of 3 mEq per kg of subject weight. The exact mEqweight of the bicarbonate compound is dependent upon the salt form(cation) used. For example, one (1) mEq of the following salts isequivalent to the indicated weight in grams:

Molecular Salt weight grams = 1 mEq Sodium Bicarbonate 84 0.084Potassium 100 0.100 Bicarbonate

As indicated above, 75% to 100% of the bicarbonate is in sodium form,and 0% to 15% in potassium form. The anionic component preferablyconsists of 100% bicarbonate (or bicarbonate equivalent, such asacetate, gluconate, citrate, and lactate). In addition to sodium andpotassium, the salt component (or cation) may include a wide varietyother suitable elements including magnesium and calcium. The anioniccomponent may also include other potassium additives, such as chloride,phosphate, pyruvate, and/or other unnamed organic anions. Preferably,25% to 40% of the total bicarbonate dosage is administered to thesubject at least 15 minutes before the bodily insult, and for amaintenance period of 5 to 12 hours after the insult.

The following examples demonstrate application of the present methodthrough oral administration of bicarbonate to the body of an 80 kgsubject.

Example 1

100% Sodium Bicarbonate: At a dosage of 3 mEq per kg, the subject takesa total of (3×80) 240 mEq of sodium bicarbonate, or (240 mEq×0.084)20.16 grams. Of this amount, (25%×20.6) 5.15 grams is administered atleast 15 minutes before the insult. Over the following 6 hours(maintenance period) after the insult, the remaining 15.45 grams isadministered at a dose rate of 2.575 grams per hour (i.e., 20.16 gramsover 7 hours).

Example 2

95% Sodium Bicarbonate and 5% Potassium Bicarbonate: Using the sameprotocol outlined in Example 1 above, the subject takes (95%×3 mEq) 2.85mEq of sodium bicarbonate and (3−2.85) 0.15 mEq of potassiumbicarbonate. This equates to (2.85×80×0.084) 19.152 grams of sodiumbicarbonate and (0.15×80×0.100) 1.2 grams of potassium bicarbonate. Theresulting total dosage is 20.352 grams. Of this amount, the subjecttakes (25%×20.352) 5.088 grams at least 15 minutes before the insult,and the remainder (15.264 grams) over the next 6 hours at a dose rate of2.54 grams per hour.

Form of the Bicarbonate Compound

The bicarbonate compound can be prepared in the following forms:

(a) For 100% Sodium Bicarbonate

Tablet: The tablet can be in any size, and provides a convenient unitfor handling. A 1000 mg (or 1.000 gram) tablet of sodium bicarbonatecontains (1.000 gram/0.084) 11.9 mEq of sodium bicarbonate. In Example1, the subject takes a total of (240 mEq/11.9) 20 tablets. Approximately5 tablets (25% of total dosage) are taken prior to the insult, and 3tablets per hour for the next 5 hours thereafter. The tablet can betaken directly by mouth or dissolved in a beverage of choice. Forenhanced mechanical stability for handling, the tablet may furthercomprise small amounts of incipient ingredients.

Powder: The powder can be weighed to a precise amount for each subject.In Example 1 above, the subject takes 20.16 grams of the bicarbonatecompound 5.15 grams 15 minutes before the insult, and 2.575 grams perhour over the next 6 hours. To facilitate handling and distribution, thepowder may be packaged in 2.575-gram packets.

Capsule: The bicarbonate can also be encapsulated in material readilydissolved in the stomach or intestine to facilitate ease of handling.

Beverage: A beverage can be provided with the bicarbonate powder ortablet added and dissolved immediately prior to use by the subject. Thebicarbonate may be mixed with water or a flavored drink like a sportdrink.

(b) For 95% Sodium Bicarbonate with 5% Potassium Bicarbonate (on a mEqBasis)

Tablet: The tablet can be in any size, and provides a convenient unitfor handling. A 1000 mg (or 1.000 gram) tablet of sodium bicarbonate andpotassium bicarbonate contains (0.9411 grams of sodium bicarbonate and0.0589 grams of potassium bicarbonate) 11.79 mEq of bicarbonate salts.In Example 2, the subject takes a total of (240 mEq/11.79) 20 tablets.Approximately 5 tablets (25% of the total dosage) is taken prior to theinsult, and 3 tablets per hour for the next 5 hours thereafter.

Powder: The powder can be weighed to a precise amount for each subject.In Example 2, the subject takes 20.352 grams of the bicarbonate compound5.088 grams 15 minutes before the insult, and 2.54 grams per hour overthe next 6 hours.

Capsule: The bicarbonate can be encapsulated in material readilydissolved in the stomach or intestine to facilitate ease of handling.

Beverage: A beverage can be provided with the powder or tablet added anddissolved immediately prior to use by the subject, as previouslydescribed.

Various exemplary embodiments of the present invention are describedabove. Use of the term “exemplary” means illustrative or by way ofexample only, and any reference herein to “the invention” is notintended to restrict or limit the invention to exact features or stepsof any one or more of the exemplary embodiments disclosed in the presentspecification. References to “exemplary embodiment,” “one embodiment,”“an embodiment,” “various embodiments,” and the like, may indicate thatthe embodiment(s) of the invention so described may include a particularfeature, structure, or characteristic, but not every embodimentnecessarily includes the particular feature, structure, orcharacteristic. Further, repeated use of the phrase “in one embodiment,”or “in an exemplary embodiment,” do not necessarily refer to the sameembodiment, although they may.

For purposes of describing and defining the present invention it isnoted that the use of relative terms, such as “substantially”,“generally”, “approximately”, and the like, are utilized herein torepresent an inherent degree of uncertainty that may be attributed toany quantitative comparison, value, measurement, or otherrepresentation. These terms are also utilized herein to represent thedegree by which a quantitative representation may vary from a statedreference without resulting in a change in the basic function or effectof the subject matter at issue. It is also noted that terms like“preferably”, “commonly”, and “typically” are not utilized herein tolimit the scope of the claimed invention or to imply that certainfeatures are critical, essential, or even important to the function oreffect of the claimed invention. Rather, these terms are merely intendedto highlight alternative or additional features that may or may not beutilized in a particular embodiment of the present invention.

For the exemplary methods or processes of the invention, the sequenceand/or arrangement of steps described herein are illustrative and notrestrictive. Accordingly, it should be understood that, although stepsof various processes or methods may be shown and described as being in asequence or temporal arrangement, the steps of any such processes ormethods are not limited to being carried out in any particular sequenceor arrangement, absent an indication otherwise. Indeed, the steps insuch processes or methods generally may be carried out in variousdifferent sequences and arrangements while still falling within thescope of the present invention.

Additionally, any references to advantages, benefits, unexpectedresults, or operability of the present invention are not intended as anaffirmation that the invention has been previously reduced to practiceor that any testing has been performed. Likewise, unless statedotherwise, use of verbs in the past tense (present perfect or preterit)is not intended to indicate or imply that the invention has beenpreviously reduced to practice or that any testing has been performed.

In the exemplary embodiments of the present invention described above,no element, act, or instruction used in this description should beconstrued as important, necessary, critical, or essential to theinvention unless explicitly described as such. Although only a few ofthe exemplary embodiments have been described in detail herein, thoseskilled in the art will readily appreciate that many modifications arepossible in these exemplary embodiments without materially departingfrom the novel teachings and advantages of this invention. Accordingly,all such modifications are intended to be included within the scope ofthis invention as defined in the appended claims.

A method for protecting nephrons against injury caused by a disruptionof the chemical environment in the kidney; a method for reducingcontrast-induced nephropathy; a safe method for administering a contrastmedium into the body of a subject; and a method for attenuating freeradical formation resulting from a bodily insult are described above.Various details of the invention may be changed without departing fromits scope. Furthermore, the foregoing description of the preferredembodiment of the invention and best mode for practicing the inventionare provided for the purpose of illustration only and not for thepurpose of limitation—the invention being defined by the claims.

1. A method for attenuating free radical formation resulting from abodily insult, said method comprising administering bicarbonate into thebody of a subject at a dosage ranging from 1.5 mEq/kg of body weight to5.0 mEq/kg of body weight within a 24-hour period, and wherein apre-insult dosage of 25%-40% of the bicarbonate is administered prior tothe bodily insult, and a remaining 60%-75% of the bicarbonate isadministered after the pre-insult dosage within the 24-hour period.
 2. Amethod according to claim 1, wherein the bicarbonate is administered ina solution comprising a bicarbonate concentration within a range of 100mEq/L and 300 mEq/L.
 3. A method according to claim 1, wherein thebicarbonate is administered in a solution comprising potassium.
 4. Amethod according to claim 3, wherein the solution comprises between75%-100% sodium and between 25%-0% potassium.
 5. A method according toclaim 1, wherein the bicarbonate is administered in a solution at avolume ranging from 4.0 to 30.0 ml/kg (of subject weight).
 6. A methodaccording to claim 5, wherein the solution is administered into the bodyat a rate of between 0.5 and 2.5 ml/kg (of subject weight)/hr.
 7. Amethod according to claim 1, and comprising continuing theadministration of bicarbonate to the subject after expiration of the24-hour period.
 8. A method according to claim 1, wherein 75% to 100% ofthe bicarbonate dosage is administered within a 12-hour period.
 9. Amethod according to claim 1, wherein 75% to 100% of the bicarbonatedosage is administered within a 6-hour period.
 10. A method according toclaim 1, wherein the dosage of bicarbonate ranges from 2.0 mEq/kg ofbody weight to 4.0 mEq/kg of body weight.
 11. A method according toclaim 1, wherein the bicarbonate is administered in a form selected froma group consisting of tablet, powder, capsule, and solution.
 12. Amethod according to claim 1, wherein the bicarbonate is administered tothe subject via an intravenous line.
 13. A method according to claim 1,wherein the bicarbonate is administered to the subject by oral intake.14. A method according to claim 1, wherein the bicarbonate isadministered to the subject via a solution comprising additives selectedfrom a group consisting of calcium-HCO3, magnesium, dextrose, sodiumlactate, potassium lactate, sodium citrate, potassium citrate, sodiumacetate, and acetazolamide.
 15. A method according to claim 1, whereinthe bicarbonate is administered to the subject via a solution comprisingadditives selected from a group consisting of chloride, phosphate, andpyruvate.
 16. A method for attenuating free radical formation resultingfrom a bodily insult, said method comprising administering bicarbonateto the body of the subject at a dosage ranging from 2.0 mEq/kg of bodyweight to 4.0 mEq/kg of body weight within a 12-hour period, and whereina pre-insult dosage comprising between 25%-40% of the bicarbonate isadministered prior to the bodily insult and a remaining 60%-75% of thebicarbonate is administered after the pre-insult dosage within the12-hour period.
 17. A method according to claim 16, and comprisingcontinuing the administration of bicarbonate to the subject afterexpiration of the 12-hour period.
 18. A method according to claim 16,wherein the bicarbonate is administered in a form selected from a groupconsisting of tablet, powder, capsule, and solution.
 19. A methodaccording to claim 16, wherein the bicarbonate is administered to thesubject via an intravenous line.
 20. A method according to claim 16,wherein the bicarbonate is administered to the subject by oral intake.